In the subspecialty of anesthesiology for orthopedic surgery, the past 12 years have provided remarkable advances in opioid-sparing analgesia via the regular use of peripheral nerve blocks. However, single injection nerve blocks with local anesthetics provide only 12 hours of analgesia, leading to little opioid sparing. As a result, continuous peripheral nerve blocks have evolved into a new "gold standard" in opioidsparing analgesia for 2-4 days after surgery. However, continuous nerve blocks with local anesthetics are expensive, labor-intensive, require subspecialty training, and have unique complications (e.g., risk of falling due to motor block). These barriers seem likely to prevent continuous nerve blocks from having an impact on public health beyond the status of a subspecialty niche. The next breakthrough in postoperative nerve block analgesia will involve single-injections that provide sustained analgesia (24-48 hours) without producing unwanted motor block or nerve damage. Sustained-release local anesthetics (e.g., microcapsulated bupivacaine) have not been successful in meeting these objectives. By combining drugs of varying mechanisms, a "multimodal" analgesic may prove to reduce or eliminate the need for postoperative opioid analgesia; if such a drug combination is both safe to the peripheral nerve and efficacious, then an important public health advance is possible. The objective of this Career Development Award is to capitalize on previous clinical research experience with continuous nerve blocks, and to supplement this prior clinical experience with 2 years of additional formal training in the basic science of nociception, analgesia, and peripheral nerve toxicology. The candidate aims to develop appropriate animal models addressing these questions, and thus accelerate scientific progress on the development of a multimodal analgesic nerve block. Such a block would further advance opioid-sparing analgesia, and aim to reduce patient dependence on opioid analgesics as the primary mechanism of analgesia in the first week(s) after orthopedic surgery. After orthopedic surgery (surgery on the bones, joints, and muscles), pain is commonly rated as "moderate" to "severe." The most common method to treat pain after surgery is with opioid analgesics (narcotics), which can both have many side effects and also be addictive. Continuous nerve blocks have helped to reduce opioid requirements, but are technically complicated and subspecialized, while local anesthetics can produce unwanted motor block that may lead to the injury of an insensate extremity. This application is presented to develop a method to improve single-injection nerve blocks, in order to provide (i) sustained pain relief after surgery, (ii) reduced motor block, and (iii) reduced opioid requirements. [unreadable] [unreadable] [unreadable]